Risk Factors of Intractable Epilepsy in Children with Cerebral Palsy

Objectives We aimed to investigate the risk factors predicting the development of intractable epilepsy in children with cerebral palsy (CP), with an emphasis on perinatal characteristics, seizure semiology, imaging, and EEG findings. Materials & Methods Following a descriptive, retrospective, case-control design, 106 children with CP and epilepsy from 2015 to 2020 were studied (46 children with CP and intractable epilepsy and 60 with CP and controlled epilepsy). Data were retrieved from medical records of participants (i.e., demographics, clinical characteristics, perinatal history, etiology of seizure and CP, seizure semiology, intellectual functions, therapeutic options, brain imaging, and EEG findings). Results We established a model of the most important risk factors that can predict intractable epilepsy in children with CP. The model included the additive effect of a poor Apgar score at 5 minutes, the presence of neonatal seizures, focal epilepsy, and focal slowing on the EEG background (Area under the receiver operating characteristic of 0.810). conclusion The findings can be used to identify intractable epilepsy in children who suffer from CP with further support by offering early therapeutic interventions intended to reduce the burden of refractory seizures.


Introduction
Cerebral palsy (CP) is a group of permanent, nonprogressive disorders that affect muscle tone as well as movement or posture. It is caused by damages to the developing brain either before or during birth (1). Motor disorders of CP are often accompanied by epilepsy, disturbances of sensation, perception, communication, cognition, and behavior, as well as secondary musculoskeletal problems (2).
It is well proved that epilepsy had a higher association with cerebral palsy; 15-60% of children with CP have been reported to be epileptics. The  (4,5,6), but also described its features, course, and outcomes, as well as consequences of refractory seizures (6). In some instances, refractory seizures are more problematic than the musculoskeletal complications of CP.
The risk factors for the development of epilepsy later in life were commonly related to earlier onset of seizure and history of neonatal seizures (7). However, data related to birth conditions contribute to a lesser extent to the development of epilepsy in these patients (8). We aimed to explore the predictive factors that increase the risk of development of drug-resistant epilepsy in children with CP Apgar scores at 1, 5, and 10 minutes, need for active resuscitation at the time of birth, and the history suggestive of hypoxic-ischemic encephalopathy, presence of neonatal seizures, history of epileptics, which was defined as a continuous seizure activity more than 30 minutes or recurrent attacks of seizures without regaining the conscious level in between (10), family history of epilepsy, history of delayed developmental milestones, EEG and brain imaging (brain CT/MRI), type, dose, and duration of antiepileptic drugs (AEDs), the response of seizure, refractory seizure, and any alternative management of seizures including ketogenic diet; vagal nerve stimulation; and epilepsy surgery, were retrieved from medical records of participants.

Materials & Methods
Controlled epilepsy was defined as experiencing no seizure for more than 12 months, while drugresistant epilepsy was defined as persistent seizures despite the proper use of at least two AEDs (proper selection--optimum serum drug level, and good compliance) (11). Also, data related to CP included the type of CP, underlying cause, and growth motor function classification system (GMFCS) score.
Assessment of intelligent quotient (IQ) was done using neuropsychological tests. Mental retardation was defined as IQ < 70. Children with IQ < 35 were defined as severe mental retardation, 49-35 was considered as moderate mental retardation, and 69-50 was defined as mild mental retardation (12).

Results
A total of 250 children with CP were recruited in the present study, of whom 130 were also suffering from epilepsy. Fourteen children were excluded from our study (2 had a neurodegenerative brain disease, one was suffering from an inborn error of metabolism, 3 had acute symptomatic seizures, 4 had isolated febrile seizures, and 4 had isolated neonatal seizures. As a result, data of 106 children with CP and epilepsy were analyzed. Prematurity was found in 23% of participants. The most common type of CP was spastic quadriplegia (31.1%), followed by spastic hemiplegia (28.3%) and spastic diplegia (16.9%). However, spastic triplegia and extrapyramidal were reported in 11.3% and 7.5% of participants, respectively. Only 4.7% showed ataxic CP. The most common cause of CP was prematurity (23%), followed by intracranial hemorrhage (20.7%) and cerebral infarction (15%). However, hypoxic-ischemic encephalopathy and central nervous system (CNS) infections were found in 13.3% and 11.3% of participants, respectively. About 10% of patients showed cerebral malformations, while 7.5% showed trauma as underlying etiology ( cases. The most common etiological factor responsible for focal-onset intractable epilepsy was intracranial Hemorrhage (22%), followed by cerebral infarction (19.5%) and CNS infection (13%). Nevertheless, brain malformation and trauma accounted for 8.7% and 4.3% of cases, respectively. The causes of CP leading to focal slowing on the EEG background in children with CP and intractable epilepsy were more or less similar, which included cerebral infarction (11%), intracranial bleeding (9%), CNS infection (4%), and, to a lesser extent, brain malformation (3%), and brain trauma (3%). Furthermore, we evaluated other variables that are reported as a probable consequence rather than a cause of intractable epilepsy. The following factors  Table 1).

Comparison of intractable epilepsy and controlled epilepsy in terms of association with independent risk factors
Intractable epilepsy in children with CP was significantly associated with a low Apgar score    (Table 3).
The additive effect of the independent variables that were more common in the intractable epilepsy group was also evaluated ( Hence, in the present study, we determined the detailed data of prenatal and postnatal problems. Few studies mentioned a positive association between birth conditions and prognosis of epilepsy in children with CP (19). However, a poor Apgar score is associated with an increased risk of developing epilepsy in the general population and for those who suffer from CP in particular (20,21,22). Previous studies mentioned the relation between gestational age or birth weight and the development of epilepsy in children with CP.
However, the results are conflicting. The association between gestational age and birth weight with intractable epilepsy was lacking in our study; however, there are studies that support our findings (18,19). According to the findings, prematurity and low birth weight were not related to the risk of developing epilepsy (18). Kulak et al.
found an increased risk of epilepsy in patients with low birth weight, but they did not reveal any association between gestational age and the risk of epilepsy development (23). Zelnik et al. reported that epilepsy was more prevalent in full-term infants than in preterm; meanwhile, they found no association between birth weight and increased risk of epilepsy development (6). In 17 European registers, some authors reported an association between epilepsy development and term and having a weight of ≥ 2500 g (15). Also, it has been reported that term delivery had a significant association with epilepsy development (24). These findings can be attributed to the fact that epilepsy usually stems from gray matter lesions, which are more prevalent in full-term babies, while white matter lesions are more common in premature infants (25,26). The increased risk of epilepsy in children with CP has been attributed to genetic and perinatal factors (4). Among the perinatal factors, brain anomalies, chromosomal defects, intrauterine infections, and neonatal HIE are the more obvious causes that may result in seizures. Brain imaging may provide a diagnostic clue to the timing and nature of the brain insult in these children (5). In our study, the type of CP or its etiology or the GMFCS score did not show a significant association with intractable epilepsy. Regarding the type of CP, some authors reported similar findings, while others found inconsistent results. The difference can be attributed to the applied methodologies (18,19). The frequency of epilepsy varies according to the CP subtype. According to the literature, epilepsy is particularly more common in patients with quadriplegic CP, while it is less common in children with dyskinetic or ataxic CP (4, 6, 24). The etiology of CP was classified according to the findings of brain imaging. It was found that children with evidence of CNS infection or brain anomalies in their brain imaging had a poor prognosis regarding seizure control compared to those with white matter injury or idiopathic causes (27). Despite the positive association between epilepsy in general and having a higher GMFCS score, our results showed an insignificant association between GMFCS score and intractable epilepsy. Contrary to our findings, Mert et al. reported an insignificant impact of GMFCS score on epilepsy prognosis (18,19,28). This can be attributed to the fact that GMFCS is a score that reflects motor system affection caused by white matter injury. Previously, it was reported that a history of neonatal seizures in children with CP is a risk factor for later epilepsy development (15,18,23,24). Going with the current evidence of epilepsy in children with CP, we found that younger age at onset of the seizure, especially neonatal-onset seizure, was associated with intractable epilepsy (29,30 (17,18,23,24,34). This can be attributed to the high number of children who suffered from spastic quadriplegic CP with diffuse brain injury in our sample of patients. There are many controversies regarding our finding that focal seizures were associated with intractable epilepsy. While some studies report similar findings (35,36), others found contradictory results (18). For instance, it has been reported that focal seizures are one of the most important predictive factors of the worst outcomes of overall epilepsy in children (36). The strong association between intractable epilepsy and focal seizure can be attributed to its association with focal structural brain lesions (37,38). This association was highlighted in our study, which showed all causes of CP that lead to focal epilepsy could be caused by focal brain pathology. Also, we

In Conclusion
According to the findings, we can conclude that the most important risk factors that can predict observed a significant association between SE and intractable epilepsy, which is supported by other studies that reported a higher incidence of SE in children with CP and considered SE as an independent risk factor for intractable epilepsy (14,30). This association can be explained by the fact that SE leads to brain damage (39). We reported changes in the EEG records in our cohort of patients in the form of generalized background slowing and focal activity. These EEG changes have been corroborated by several studies (4,16,23,34,35).
In our study, EEG changes that are predictive of intractable epilepsy were focal, multifocal discharges, and focal background slowing. These EEG changes are an indication of intractable epilepsy in epileptic children (43,44